Art formulation technology has addressed the need for improving the absorption of hydrophobic substances. The focus of this work has concerned the use of polyethylene glycol (PEG) as a surfactant, creation of microsdispersions to reduce particle size and the use of spray drying techniques to form discrete particles.
The early work with PEG is exemplified by the patent by Riegleman and Chiou which included the intimate association of poorly soluble drug with soluble PEG carriers for enhanced absorption (U.S. Pat. No. 4,151,273). The usual technology in such formulations was to combine a heated mixture of PEG or polyvinylpyrrolidone with poorly soluble drug, followed by subsequent cooling to form a "solid solution" of dispersed drug. This solid mixture or dispersion was subsequently ground into a fine powder for tableting. The enhancements of this technology concerned the preparation of various liquid or oil based dispersions or emulsions of insoluble substances for oral administration. The technology for the creation of finer particle size in dispersions was subsequently described for excipient systems of lipids and surfactants promoting reduced particle size (U.S. Pat. No. 4,880,634). The addition of free fatty acids and phospholipids to emulsion forming technology was then described for better compatibility with intestinal micelles (U.S. Pat. No. 5,314,921). More complex emulsions and multiple emulsions in digestible oil were most recently described as variations on this theme (U.S. Pat. Nos. 5,645,856 and 5,583,105).
The technology of mixing hydrophobic substances in coating materials, described by Sair and Sair (U.S. Pat. No. 4,230,687), has been the basis for creating various forms of stable microdispersions using mechanical mixing in various polymeric encapsulating materials such as starch, gum or protein. However, this technique requires thick mixtures of starch in order to preserve the discreet microdispersion particles. Enhancement of oral uptake was achieved for dipyridamole by the creation of an amorphous, non-crystalline mixture with polyvinylpyrrolidone as the emulsifier, followed by spray drying the mixture (U.S. Pat. No. 4,610,875). The process of spray drying an emulsion of lecithin, organic oil and a non-ionic poloxamer surfactant was developed for the creation of shelf stable flavorants in the food industry (U.S. Pat. No. 5,362,425). Improved particle formation for insoluble drugs was later described which included the use of carboxylic acid esters of PEG, like vitamin E succinate PEG 1000 ("TPGS"), as emulsifying agents and a coating material mixed prior to spray drying to form particles (U.S. Pat. No. 5,430,021).
TPGS has been independently explored as both a water-soluble form of vitamin E and as a means of creating liquid emulsions in combination with hydrophobic drugs or vitamins. This use has provided for applications to increase the uptake of vitamin D and poorly soluble drugs such a cyclosporine (Argao et al., "d-.alpha.-Tocopheryl Polyethylene Glycol-1000 Succinate Enhances the Absorption of Vitamin D in Chronic Cholestatic Liver Disease of Infancy and Childhood," Pediatric Research, 31:2, 146 (1992)). TPGS and related food grade PEG esters have proved to be useful as a means of increasing the absorption of the esterified vitamin E as well (U.S. Pat. No. 5,179,122). Other formulations of TPGS in combination with non-esterified vitamin E have been developed by mixture of TPGS with flow enhancing agents and spraying (U.S. Pat. No. 5,234,695). In these uses TPGS had been employed as an emulsifying agent which improves intestinal absorption. However, this function is not unique to TPGS as use of the unrelated Milk Fat Globule Membrane lipid fraction from cow's milk has shown, in which an emulsion increased the uptake of cyclosporine to a similar degree (Sato et al., "Enhancement of the intestinal absorption of a cyclosporine derivative by milk fat globule membrane," Biol. Pharm. Bull. 17(11), pp. 1526-1528 (1994)). The most recent work with TPGS explored the mechanism by which this PEG ester increased the bioavailability of cyclosporine.
Measurement of cyclosporine metabolites revealed that TPGS did not effect the action of CYP 3A4 enzymes and instead implied that in addition to enhanced solubilization there must be a second mechanism by which TPGS acts in order to account for the degree of enhanced drug uptake observed. It was speculated that this mechanism may involve inhibition of the p-glycoprotein pump. (Chang et al., "The effect of water-soluble vitamin E on cyclosporine pharmacokinetics in healthy volunteers," Clinical Pharmacology & Therapeutics, 59:297-303 (1996)).
Based on the evidence supporting the use of dietary phytochemicals to shift estrogen metabolism to more beneficial metabolites like 20 H-estrone, the need exists to develop safe and effective formulations for dietary supplements. The preferred dietary phytochemicals for enzyme induction, like DIM and chrysin, are highly insoluble and subject to anti-absorptive mechanisms which limit oral bioavailability. Therefore, the need exists for formulation technology and preparations of phytochemical combinations which overcome the barriers to their absorption.